Transluminal coronary angioplasty was introduced in the late 1970's as a nonsurgical treatment for obstructive coronary artery disease. Typically, the procedure involves placing a balloon-tip catheter at the site of occlusion, and disrupting and expanding the occluded vessel by inflating the catheter balloon. Since its introduction, major advances in equipment and techniques have led to widespread use of the method for treating coronary artery disease and angina. Recent studies have reported an equivalent seven-year survival rate for percutaneous transluminal coronary angioplasty (PTCA) and bypass surgery in patients with multivessel coronary artery disease. The process, however, damages the blood vessel wall, including loss of the endothelial lining of the vessel. Frequently the response to this injury includes myointimal hyperplasia, proliferation of fibroblasts, connective tissue matrix remodelling and formation of thrombus. These events lead to restenosis of the blood vessel, a segmentally limited, wound healing response to trauma of the vascular wall. This healing response leads to narrowing of the lumen of the vessel wall and hence to a high incidence (30 to 50%) of restenosis (Fischman et al., Serruys et al.).
Clinical trials in restenosis prevention using various revascularization devices, antiplatelet drugs, antithrombotic drugs, and anti-inflammatory agents have produced limited improvement in the incidence of restenosis. Attempts to improve the risk or severity of restenosis have employed intravascular stents (e.g. Savage, Rubarteli, Gottman), radiation therapy (Koh), and/or administration of anti-proliferative drugs at the vessel injury site. The latter approach typically employs the balloon catheter for introducing the therapeutic agent at the vessel occlusion site (Dick, Roy, Dev, Alfke, Robinson, Barath, Herdeg, Pavlides, Oberhoff, Hodgkin), or releasing drug from an implanted stent (Teomin, Bartonelli, Raman).
The use of coronary stent implantation has reduced the rate of angiographic restenosis to the low teens in large arteries. Coronary stents provide luminal scaffolding that virtually eliminates elastic recoil and remodeling. Stents, however, do not decrease neointimal hyperplasia and in fact lead to an increase in the proliferative comportment of restenosis (Edelman et al.).
Drug coated or drug impregnated stents deployed within the lumen of the blood vessel have been widely explored as drug delivery devices. The drug is gradually eluted from the stent and diffuses into the vessel wall from the intima. Examples of drugs used to coat stents include rapamycin (Sirolimus®, Wyeth Ayerst), a macrolide antibiotic with immunosuppressive properties, paclitaxel (Taxol®, Bristol-Myers Squibb), and actinomycin D, both chemotherapeutic agents. All of these have been shown to inhibit smooth muscle cell proliferation in such settings (Herdeg et al., 2000; Suzuki et al., 2001; Drachman et al., 2000; Hiatt et al., 2001).
However, with increased use of stent implantation, the frequency of in-stent restenosis also increases. There is evidence that the degree of inflammation and subsequent neointima formation is proportional to the degree of penetration of the vessel wall by the stent struts (Herdeg et al.). Regardless of treatment strategy (e.g. PTCA, rotational atherectomy, laser angioplasty, cutting balloon angioplasty, or repeat stenting), the restenosis in case of in-stent restenosis is unacceptably high (20 to 80%).
Other limitations of drug-eluting stents include limitation of drug loading capacity and poor control of drug elution, resulting in unreliable pharmacokinetics. The devices are typically coated with biocompatible polymers, and durability of the polymer coatings has been problematic. The thickness of some currently used coatings makes these devices unsuitable for very small vessels. Finally, most of the current coatings are prone to causing chronic inflammatory responses. Other long term effects of the devices can include late thrombosis, weakening of the vessel wall, or delayed restenosis. Thus, long term follow-up is necessary to monitor the polymer's potential toxicity. Treatment with coated stents can also be costly, especially in cases where a multi-stenting procedure is planned.
Intracoronary brachytherapy (Leon et al., Malhotra et al.) is a current approach to prevention of renarrowing of an artery after angioplasty or stent placement. A small amount of radiation is delivered to the treated area, either via catheter, which delivers radiation to the treated area and is then removed, or via a radiation-emitting stent, which remains in place. Although shown to be effective in reducing the need for additional treatment of in-stent restenosis, the procedure may be associated with other complications. Weeks to months after brachytherapy, restenosis may occur at the edges of the treatment areas. Low-level radiation that penetrates beyond the targeted treatment area increases the growth of the soft tissue, resulting in narrowing, which is known as the “candy wrapper” or “edge” effect (Albiero et al.). Such edge effects can also occur with drug-eluting stents, since the drug is not available beyond the edges of the stent.
Vascular occlusive phenomena also occur in other therapeutic settings. Autologous vein grafting, for example, is widely employed in coronary bypass procedures. About 400,000 to 500,000 first-time coronary graft procedures are performed every year in the United States alone. Although patient survival rates exceed 90% over the first five years after treatment, about 20% to 40% of the grafts fail during this time due to occlusive phenomena. Thus, 80,000-100,000 graft replacement procedures are needed in the U.S. yearly to avoid premature mortality.
Vascular occlusive phenomena also lead to failures in other vascular grafts, such as arterial-venous anastomosis used for kidney dialysis, and in organ transplants. In the vascular access model of kidney dialysis, a surgically formed arterial-venous anastomosis or shunt provides access to the artery and vein used for dialysis. During dialysis, the rate of blood flow, turbulence and stress at the venous junction is much higher than in a normal vein. Repeated exposure to these pressures frequently leads to hyperplasia and stenosis within the vein, causing dialysis access failure.
Accordingly, the incidence of restenosis, and the inability to predict the response to treatment, remains a serious risk factor in vascular angioplasty and other vascular surgical procedures.